The action of many known cannabinoids can be attributed to their interaction with cannabinoid receptors. The discovery that cannabinoid receptors are present in mammalian systems has led to further research. For example, there has been identified a class of G-Protein coupled receptors which are present mainly in the central nervous system, these have been named CB1 receptors.
Another type of G-Protein coupled receptor is the CB2 receptors which are found substantially in the immune system.
Cannabinoids are generally cannabinoid receptor agonists, which mean that they dock with a cannabinoid receptor and activate it.
Well known cannabinoid receptor agonists include the classical plant derived cannabinoid delta-9-tetrahydrocannabinol (THC), the non-classical cannabinoid receptor agonist R-(+)-WIN55212 and the eicosanoid or animal derived cannabinoid receptor agonist anandamide. All of these compounds have been shown to bind to the CB1 receptor.
Agonism at a receptor will often lead to an active response by the cell. Many disease states result from the overactive or overabundant effects of agonists at their receptors.
Research has led to the discovery of compounds that prevent the activation of cannabinoid receptors and as such are known as cannabinoid receptor antagonists. A competitive antagonist of cannabinoid receptor is one that will bind to the receptor but not cause a response in the cell. An inverse agonist acts upon a receptor to produce an opposite effect to the response that the agonist would produce.
The compound SR141716A (described in EP0576357) has been shown to antagonise the CB1 cannabinoid receptor. There is evidence however that SR141716A is an inverse agonist rather than a silent or neutral antagonist (Pertwee, R. G., 2003).
Maruani and Soubrie in U.S. Pat. No. 6,444,474 and EP0969835 have described the use of an inverse CB1 receptor agonist such as SR141716A in the regulation of appetency disorders.
In many CB1-containing assay systems, SR141716A by itself produces effects that are opposite in direction from those produced by CB1 agonists such as THC. Therefore leading to the inference that it is an inverse agonist of the CB1 receptor. Whilst in some instances this may reflect antagonism of an endogenous CB1 agonist (a CB1 agonist produced by the assay system itself) in other instances it is thought to arise because CB1 receptors are constitutively active.
It is generally considered that constitutively active receptors trigger effects even in the absence of any administered or endogenously produced agonist. Agonists enhance this activity whilst inverse agonists oppose it.
In contrast, neutral antagonists leave constitutive activity unchanged. Neutral antagonists are favoured over inverse agonists as they only block the ability of the receptor to interact with an endogenously produced CB1 agonist such as anandamide or one that has been administered.
There is evidence that the endogenous CB1 agonist, anandamide, may be released in the brain to mediate processes such as feeding and appetite (Di Marzo et al., 2001). This raises the possibility that an antagonist of this receptor could be effective in the clinic as an appetite suppressant.
The compound SR141716A engages with the CB1 cannabinoid receptors so that they can't be activated. It is possible that blocking the CB1 receptor system may adversely affect CB1 mediated aspects such as mood, sleep and pain relief.
As endocannabinoids have neuroprotectant and anti-oxidant properties it is also possible that users of SR141716A may be at an increased risk of cancer and stroke.
Neutral CB1 receptor antagonists are likely to have a less complex pharmacology than those of an inverse agonist. Thus, when administered by itself such an antagonist will only have effects in regions of the cannabinoid system in which there is ongoing release of endogenous cannabinoids onto CB1 receptors but will not affect the activity of the endogenous cannabinoid system that arises from the presence in some parts of this system of constitutively active CB1 receptors.
CB1 receptor antagonists, particularly neutral CB1 receptor antagonists, are as such, likely to be useful in the treatment of diseases and conditions that are caused by an interaction with the CB1 receptor. Such diseases and conditions include, for example, obesity, schizophrenia, epilepsy or cognitive disorders such as Alzheimers, bone disorders, bulimia, obesity associated with type II diabetes (non-insulin dependent diabetes) and in the treatment of drug, alcohol or nicotine abuse or dependency (Pertwee, R. G., 2000).
The use of a neutral antagonist in place of an inverse antagonist would be particularly beneficial, as it is likely that fewer side effects would occur since it would not augment the consequences of CB1 receptor constitutive activity.
At the present time there are few identified neutral CB1 receptor antagonists. An analogue of the psychotropic cannabinoid THC has been produced which behaves as a neutral CB1 antagonist in vitro (Martin, B. R. et al. 2002). The compound, O-2050 is a sulphonamide analogue of delta-8-tetrahydrocannabinol, and has acetylene incorporated into its side chain.
This analogue behaves as a neutral CB1 receptor antagonist in the mouse vas deferens. However, O-2050 does not behave as a CB1 receptor antagonist in mice in vivo and, like established CB1 receptor agonists, it depresses mouse spontaneous activity. Moreover, analogues of O-2050 with R=ethyl or R=butyl behave as typical CB1 receptor agonists in mice in vivo.
Surprisingly the applicants have shown that the cannabinoid tetrahydrocannabinovarin (THCV) is a neutral antagonist of the CB1 and CB2 cannabinoid receptors.
The cannabinoid THCV is a classical plant cannabinoid, which is structurally related to THC, in that instead of the 3-pentyl side chain of THC, the THCV molecule has a 3-propyl side chain. The structures of the two cannabinoids are shown in FIG. 1.
The finding that THCV appears to act as a neutral antagonist of CB1 receptors was particularly surprising as THC is known to be a CB1 agonist and it should therefore follow that a structurally related compound such as THCV would also be an agonist rather than an antagonist.